Phototherapy for neonatal jaundice (hyperbilirubinemia) is the most widely and frequently employed treatment to remove or accelerate the excretion of unconjugated bilirubin from the body and reduce the risk of bilirubin-related brain damage. (Bilirubin is a lipophilic, neurotoxic metabolite produced in copious amounts in mammals by degradation of heme. Under normal metabolic conditions it is detoxified by glucuronidation in the liver and excreted in bile. However, newborns develop transient unconjugated hyperbilirubinemia shortly after birth (physiologic jaundice) due to a transient maturational insufficiency of hepatic UDP-glucuronyl transferase.) Although much is now known of the major photochemical mechanisms important to the success of phototherapy, it has become increasingly clear that the overall mechanism depends crucially on allosteric effects--the relationship between 3-dimensional molecular structure and the control and development of intrinsic macroscopic properties such as solubility and binding. This proposal focuses on this very important facet of phototherapy, and our proposed studies will therefore attempt to provide an understanding at the molecular level of: (1) how (extravascular) albumin plays a major role in phototherapy by binding to bilirubin, thereby selecting and directing the course of its photochemistry; (2) the role of serum albumin in selective binding, preserving pigment conformational stereochemistry, and transporting bilirubin photoproducts to the liver; and (3) how 3-dimensional structure determines intrinsic excretability and/or conjugation of bilirubin and its photoproducts. The overall long-term objectives of this application are to understand the how phototherapy works at the molecular-structural level. The studies will involve organic synthetic, biochemical, spectroscopic, chromatographic and metabolic techniques. They are particularly relevant to ordinary aspects of bilirubin metabolism, including serum albumin stereochemistry and binding and liver metabolism.